Methamphetamine (MA) addiction is a public health concern that causes substantial harm to individual users, and imposes an economic burden in the U.S. totaling up to $48.3 billion annually. This application addresses a critical aspect of thi problem: the lack of any proven, FDA-approved pharmacological treatments for MA users. The proposal combines an intervention designed to improve energy metabolism in the brain, and a neuroimaging technique capable of measuring the neurochemicals that represent cerebral bioenergetic function. The study will replicate and extend a key neuroimaging finding recently reported by our group: that MA users have decreased phosphocreatine (PCr) levels in the brain, compared to healthy volunteers. PCr is the substrate reservoir for the creatine kinase reaction, which reversibly converts PCr into adenosine triphosphate (ATP), the brain's major energy supply, and creatine. Neuronal energy demands are met through a shift in reaction equilibrium, which is designed to maintain the concentration of ATP constant. We also showed that female MA users have lower brain PCr levels compared to male users. These findings join the converging lines of evidence that MA use is associated with mitochondrial dysfunction, i.e. deficient energy metabolism, in the brain. Frequently, MA users also experience depression, as well as cognitive deficits. Interestingly, both of these entities are also linked to mitochondrial dysfunction in the brain. The long-term goal of this research program is to define the alterations in brain chemistry that underlie MA use disorders, and to utilize translational magnetic resonance spectroscopy (MRS) neuroimaging to identify rational brain-based treatment targets. Once a hypothesis-driven intervention is identified, MRS can then be further employed in treatment studies, to verify that target engagement is achieved. The specific aims of this proposal are an example of this stepwise scientific process: the nutritional supplement creatine will be tested in an open-label study of women with MA use disorders, to investigate creatine's effect on cerebral PCr levels, depressive symptoms, and MA usage. Over a 2-year period, the project will enroll 10 women between the ages of 18 and 64 with MA use disorders and depression, and the women will be treated with 8 weeks of creatine. Neuroimaging will be performed at baseline, and repeated after 8 weeks of treatment, to test the hypotheses that creatine is associated with: (1) increased PCr concentrations; and (2) reduced depressive symptoms.